Greater than half of all cancer patients receive radiation therapy, thereby emphasizing the need to understand the cellular and molecular events following exposure. In response to certain environmental stresses, such as ionizing radiation (IR) a class of proto-oncogenes referred to as early response genes are activated. These genes encode nuclear transcription factors involved in the transmission of inter- and intracellular information through signaling pathways. The aberrant expression or regulation of these factors is not only a key step in carcinogenesis, but also appears to be a specific determinant of tumor cell response to anti-neoplastic therapies. In this regard, these gene products may function in coupled short-term changes in cellular phenotype by modulating the expression of specific target genes involved in cellular defenses to the damaging effects of IR. Hence, the upstream signaling factors that regulate and activate of these nuclear transcription factors and the subsequent expression of their specific target genes provide an ideal model system to study the molecular and biochemical events responding to IR. We are investiging the role of the redox-sensitive signaling factors thioredoxin reductase and thioredoxin as radioprotective factors in cancer cells and their value as molecular targets to sensitize tumors to the cytotoxicity of ionizing radiation.